Though antidepressant drugs are effective in most persons with depression, the delayed onset of action results in significant complications, including: (1) reduced compliance, (2) slowing of the return to normal social/ occupational functioning, (3) increasing the risk of suicide, (4) contributing to cumulative hospital costs, and (5) prolonging the duration of suffering. There is thus a need for a maneuver that would speed the clinical response to antidepressants. One night's whole sleep deprivation (SD) is known to produce a significant, albeit transient, antidepressant effect. This project will study the potential for the prolongation of the response to SD by combination with imipramine (IMI). In addition, the hypothalamic-pituitary-thyroid axis is significantly involved in the regulation of the mood, and changes in this system are known to be related to response to SD. The specific aims of the project include: (1) comparing the antidepressant effects of three treatment groups in patients with major depression: (a) IMI + SD, (b) SD alone, and (c) IMI alone (to test whether IMI will extend the antidepressant response to SD); (2) evaluating thyroid hormone function (i.e., TSH, delta max TSH after TRH, T3, T4, FT4-index, antithyroid antibodies [ATA], and thyroid binding globulin [TBG] before and after SD to assess whether thyroid function values are associated with response to SD; (3) investigating the relationship of both SD response and thyroid activity with antidepressant treatment outcome at day 28. 195 depressed persons aged 18-65 with a DSM- III-R diagnosis of major depression will be studied over a five year period. The patients will be randomly assigned to one of the three treatment groups. After initial assessment, patients will receive baseline thyroid testing (including T3, T4, TSH, ATA, TBG, and TSH response to TRH). After a minimum of five days, the subjects will undergo a one night's observed SD, with replication of the thyroid testing the next morning. They will then be randomized into the three treatment groups, and treated for a total of 28 days, while being rated on the Hamilton Rating Scale for Depression, the Beck Depression Inventory, and a rating specifically designed for this project the Sleep Deprivation Depression Rating Scale, at baseline and on SD + 1 - 10, 14, 21, and 28 days. Appropriate statistical comparisons will be made to evaluate the specific aims.